| Version 2.5.2.0 |
|
|
Abstract
Grant Number: 1R03MH084835-01 Project Title: Interdicting Eukaryotic Translation Initiation Factor-RNA Interaction
PI Information: Name Title PELLETIER, JERRY jerry.pelletier@mcgill.ca PROFESSOR Abstract: DESCRIPTION (provided by applicant): Translation is an essential cellular process whose deregulation is associated with alterations in cell growth, cell cycle progression, and cell death responses. The initiation phase of translation is a key target for regulation when cells are exposed to various environmental cues (e.g. - insulin, amino acid starvation, mitogenic stimulation, hypoxia, etc). As well, translation initiation control is usurped upon viral infection and is deregulated in many human cancers. Over-expression of certain translation factors can lead to malignant transformation and many of the components of the translational apparatus are over-expressed in human cancers. Several tumor suppressor genes directly influence the translation process and recently, chemoresistance in vivo has been linked to deregulated translation initiation. In a transformed setting, where translation can be inhibited by a small molecule modulator (e.g. rapamycin), decreased translation rates are associated with reversal of chemoresistance, possibly by inhibition of pro-survival pathways or resetting of pro-apoptotic program. These results validate translation initiation as a potential chemotherapeutic target. The Specific Aims of the current application are to implement a High Throughput Screen (HTS) at the MLSCN in order to identify small molecules that block translation initiation by targeting two important components of this pathway - eIF4H and poly(A) binding protein [PABP]. Both proteins require RNA binding to mediate their effects on translation initiation and our screens are designed to block this process. In addition, both screens can be used as counterscreens for each other to eliminate non-specific inhibitors. We have secondary nitrocellulose binding assays and tertiary crosslinking analyses that can detect the binding of initiation factors to mRNA as a means of confirming true "hits". Follow-up studies with optimized compounds will be performed to characterize their biological properties in vitro and in vivo. The therapeutic potential of inhibitors of eIF4H and PABP that show activity in vivo will be assessed in a number of setting, including potential to curtail, or delay, Herpes Simplex Virus infection (where eIF4H has been implicated), as well as synergize with conventional therapies in a mechanism-based mouse cancer model. Specifically, we will test the ability of identified inhibitors to synergize with conventional "standard of care" agents in lymphomas of defined genotypes generated in the E5-myc mouse cancer model. PUBLIC HEALTH RELEVANCE: Compounds identified in this screen will affect targets involved in regulating translation initiation, a process that is frequently usurped upon viral infection of cells, as well as in cancer cells. Therefore these compounds have the potential to act as anti-viral or anti-cancer agents. In addition, since this target of these compounds resides downstream of the target of rapamycin (called TOR), these may be of use against rapamycin-resistant cancers.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution: MCGILL UNIVERSITY 845 SHERBROOKE STREET WEST MONTREAL, PQ H3A 2T5 Fiscal Year: 2008 Department: Project Start: 26-AUG-2008 Project End: 31-JUL-2009 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZRG1